>> welcome to the broadcast. foanlts a charlie rose special -- tonight a charlie rose special edition. in the sixth episode of the charlie rose brain series, we look at the aging brain. >> it's extremely important to be intellectually active. and continue your career as long as you can possibly carry it on and do other things that give you intellectual pleasure. linda feed who is the dean at the school of public health in columbia is interested in cognitive function aging and she found if you take people in their 0's and put them -- 70's and put them into elementary schools as assistance, a volunteer core their intellectual function tends to persist on a fairly high level compared to controls that don't do this. so cognitive involvement particularly in social situations is very very helpful. and certainly social involvement is extremely important. >> the sixth episode of the charlie rose brain series underwritten by the simons

foundation, coming up.

captioning sponsored by rose communications from our studios in new york city, this is charlie rose. >> charlie: tonight we continue our journey through one of the most cutting evening fields in science, the brain. last month we looked at how the brain develops during infancy and childhood. tonight we turn from the developing brain to the mature brain. our subject, the aging brain. the study of aging is more important today than ever. over the past century life expectancy has sky rocketed thanks to a broad range of medical advances.

the average american born today is expected to live for nearly 80ers. but as we expand the life of the body, we must also extend the life of the mind. with old age comes wisdom and maturity. however there's also the deterioration of many cognitive abilities, the aging process affects memory in particular. alzheimer's disease, dimension and age related memory loss are reaching epidemic levels. but cutting edge research shows that these diseases may one day be preventible. like every other brain function, memory is controlled by biological mechanisms decoded by science. over the past century our understanding of memory has increased exponentially. we now know that memory comes in many many different forms, each controlled by different brain systems. aging degrades certain types of memory while leaving others in tact. joining me this evening is a remarkable group of scientists who have devoted their careers

to understanding memory and the aging brain. they are brenda milner. she is one of the pioneers in this field. her experiments in the 1950's formed the basis for the modern theory of memory. she is the dorothy killum professor of neuroscience and a professor in the department of neurology and neurosurgery at mcgill university. larry squire, his work has shown us that not all memories are the same. in the 1980's he began categorizing memories according to their content, their purpose and their locations in the brain. he is a professor at the university of california san diego school of medicine and a scientist at the veteran's affairs medical college in san diego. john hardy, his research into the genetics of alzheimer's disease has given hope to millions. in 1992, he discovered a genetic mutation responsible for the plaque that accumulates in alzheimer's disease. he's a over of neuroscience at university college london.

scott small, he uses brain imaging techniques to study how the brain changes in old age. he is suching for behaviors, foods and drugs that might prolong our mental acuity. he is an associate professor at columbia university. and once again, my cohost is dr. eric kandel. he is a noble laureate, a professor at columbia university, a howard hughes medical investigator and the man who is the inspiration, the guide, the spirit of this series and it's always good to have him right here in this studio. >> pleasure to share this with you charlie. >> charlie: what's important to understand about the aging brain. >> there is good news about the aging brain. we are living longer as you indicated and we're living better. because of public health measures, improved diet, increased exercise that people do, increase social involvement. people live better lives. one thing that interferes a

number of instances with people to live productive mature lives as they age is interference with memory. memory is very susceptible to age. and therefore one of the issues we want to address is what is the nature of memory. what is the biological base of memory. where is memory localized in the brain. as we discussed in earlier programs. we now know that most mental functions are localized to specific regions or combinations of regions in the brain. the amazing thing is until 1950, there was question whether memory storage could be localized to a pick region. people thought it could not. and the then two major heroes, the two heroes of the memory storage emerged, walter penfield and brenda milner. walter penfield, an extraordinary neurosurgeon who trained with harvey curbing and

also trained with sharington. one of the pioneers and really showed you continuity in scientific research. great scientists don't simply do great science, they also train other great scientists. the specialty that pen field developed was to operate on people with epilepsy. and he developed a particular procedure for doing that. he developed a procedure whereby he operated on people who were not annett anesthetized. it's marvelous you can operate on people's brains while they're talking to you. they have a preparation talking back to you. working with monkeys and cats, i never had that. what he did was infiltrated the scalp with a local anesthetic. he exposed the bone of the school and then he exposed the brain. in order to make sure that he does not damage normal parts of the brain, he stimulated the

surface of the cortex. his specialty was epileptic surgery. only many of these came -- many of these came from scar tissue on different parts of the brain. to make sure it didn't damage for example areas involved in speech which indicated in the orange circles on the right image, he stimulated different parts of the brain to see what the person's response was. we see on the left, the right hemisphere and we see here on the right, the left hemisphere. when he stimulated area of the touch area of the brain. patient felt touch sensation. not surprising. stimulated the motor area, patients had movements of their hands. but when he stimulated the temporal lobe which indicated here in these green markings, he found an amazing phenomena which he calls experiential responses. the patient would all of a sudden say, you know, something is coming back to me as if it's

a memory. i hear sounds, songs, parts of symphonies. one person said i hear the lullaby my mother used to sing to me. amazing. another person said the segment of the symphony that i loved when i was young is coming back to me. so he realized he was getting close to something related to memory. he called in brenda milner, an extraordinarily gifted young psychologist and she worked with penfield and they showed that the temporal lobe particularly its medial surface is involved in memory. and they make several absolutely striking discovers. they found that if you resected the temporal lobe on one side for surgery, you could stop the epilepsy. but you didn't interfere with memory at all. if for example you removed one side but the other side was damaged so the person had an interference with both temporal lobes, the person actually had a

significant memory loss. he could no longer convert short term memory into long term memory. penfield verified this. he got a call from a neurosurgeon in new haven called william so field who operated on both sides of the temporal lobe and he left the patient watt any seekers. this is a very famous patient but the person had enormous difficulty brenda found in converting new short term memory to new long term memory. he would meet brenda repeatedly but each time she walked into the room as if he met her for the first time. for the longest time she thought this applied to all areas of knowledge. that the medial temporal lobes are required to convert short term to long term memory. then she made another discovery. she found in terms of certain, a certain motor skill, hm could do it as well as you and me. so he retained certain memory

capabilities perfectly well. larry squire entered the scene and began to explore this and found it wasn't limited to motor skills, there were whole families of perceptual and motor skills that people with medial temporal lobes lesions, bilateral, could perform perfectly well. and that made him realize there are two major memory system in the brain. those that involve the medial temporal lobe he called this declarative memory, a memory for people, places and objects. and there were family of skills called non-declarative memory, motor perception skills, hitting a tennis ball, golf swing. you and i are talking to each other. we're using the english language. it is presumably grammatically correct. but neither you nor i are paying attention to my grandma. it is implicit. a remarkable insight. once we knew about these two memory systems, the question

arose how do they age. how do they handle the aging process. it turns out the implicit memory system, the non-declarative system handles aging quite well. but the declarative memory system which involves the medial temporal lobe is quite sensitive to the aging process. and it's susceptible to two kinds of disturbances. a graduate progression called age-related memory loss and a very serious rapid progression called alzheimer's disease. we're going to discuss the differences between them and we have here john hardy who discovered the first gene absolutely critical for alzheimer's disease and he showed exactly how it works. this is responsible for terrible plaque deposits that is responsible first for killing synapses and then nerve cells. moreover, now that we understand something about memory loss, we want to understand how do we keep it. how do we keep intellectually

engaged. we realize that several things are very helpful. intellectual involvement, social involvement and physical fitness. so we really want to under is what allows brenda milner at age 91 to be the most intellectually capable person at this table. >> charlie: all right, we're going to meet in just a second and pick up the chris conversatn with breb demill brenda milner e might say shawr as a tack. here is a book. every month you bring me a book and this one is by penfield in which it's called the excitable cortex in conscious man, a series of lectures i guess that he gave. what's amazing to me is that we have in every instance or in many instances found out that these people on the frontier were an amazingly press yenent d with later evidence with all kinds of techniques and new studies and imaging showed how good they were, even though they

were working a number of decades ago. it's amazing. >> this is why they called the giants of science. they not only have insight into what the immediate findings mean but they can extrapolate them for their implications. sharington made a an impact. we're still living in the pen field milner area. >> charlie: this is really interesting stuff here. we begin with the remark many brenda milner at our table for a conversation about these themes that we just were introduced to. here is brenda. >> my task was to explore the functions of the human temporal lobe about which really very little was known. and so then we see the left left hemisphere of the typical brain and we see the red areas of the speech areas in the left hemisphere which we've already seen from dr. kandel. the typical temporal, and this

is the first important point that you do for the treatment of epilepsy and it's still very successful way of treating even helpity to this day i in this kd in one lobe. it's unilateral that is to sate surgeon operates on one half of the brain and the other half is assumed to be functioning normally. we are able to compare the effects of removals in the left hemisphere with those in removal on the other side. there we've got to gain an instance of vocalization if function within the memory. there was small memory changes. if it was from the left side, it was to do with memory for words, for language. if it was from the right side, it was affecting a little one's memory for faces and places and tunes. non-linguistic. but these cheeksz were very mild effects. it was not anything of which the patients particularly

complained. and often was present anyway before the surgery. in exchange for that, the control of the eve epilepsy if t was successful and it usually was, was changing the quality of life and often showing improvements on general tests of intelligence. and all this was going very smoothly and i was collecting all my results, my group data when suddenly weeds real great surprise and -- we had great surprise and for dr. pen field and great and pleasant shock. when one patient, an engineer 46 year old engineer whom we called pb from new jersey came to have a left temporal removal. he came back and had his operations in two stages because the first superficial one had not cured him. after the second operation this highly intelligent man who was tested preoperative extensively said an raleigh what have you

people -- angrily, what have you people done with my memory. we had a continuous amnesia, forgetting the events of his life as he moved forward so he couldn't remember if his wife had been to see him that day, he couldn't remember what he had for breakfast. he said he woke up in the morning, it was buzzing, booming confusion. but then in his case, gradually he would say that right now everything is clear. and all these patients, actually that i have seen with this kind of amnesia, this kind of forget untilness say this. right now everything now everything is clear. we have short term memory is preserved but we have this inability to transfer information into a long term storage. now we had this patient and wondered why we lost his memory and very worried and a month later we had a similar case. and at that point, dr. penfield was very worried but also very excited and interested as we both were. and so we reported these two

findings and they're meeting in chicago. but we had to come up with some explanation and the explanation that we offered was that perhaps because we couldn't see into the brain beforehand and because we never saw the other side, we only saw the left side. perhaps in these two patients there was some, there was some scawrg, there was some damage -- scarring, there was some damage in the media temporal region of the opposite hemisphere on the right hemisphere which was not operated on by dr. penfield. >> it's the first demonstration that one could localize the memory function to the specific region of the brain. >> yes, yes. and so we reported these cases with this hypotheses. it was just conjecture for us in those days. and then dr. penfield got a telephone call from a neurosurgeon in hartford connecticut dr. william scold who called and said i read the abstract with interest because i think that the memory loss that you are describing, your two

patients is similar to the memory lots that i have seen -- loss i have seen in a patient and whom i carried out my operation. dr. scold's operations were different. first of all he was operating on both sides of the brain. our operations in montreal were on one side with the hypotheses that was damage on the other. here we're operating just on both sides. it differed also in thought involving the lateral cortex, the lorl surface. the -- lorl latera lateral surf. you see the normal healthy brain and the patient hn which is a section through and you're looking through the two hemispheres and you can see that the medial structures, the midline structures in h nsmght -- hn which has been removed. now what about the patient because dr. scofield invited me to go down to hartford, connecticut and study these patients and others.

when i met him, i used to go around talking about this young man but he died recently at the age of 82. and he was 29 when i met him in 1955. now hm also had seizures, epileptic seizures and at the age of 16 he began having major, really major convulsions, really very very serious epilepsy and it was treated with the maximum doses of the medications available in the day and it didn't make any difference. he had great difficulty although he was brate, finishing high -- bright, finishing high school, he had great difficulty keeping a job. because he was having these big attacks and falling and so on. during this period, dr. scofield suggested that perhaps this operation might help his epilepsy. he suggested that because he was impressed by the work that was coming out from montreal by

dr. pen field, whose work was very pioneering. scofield was impressed that perhaps even though this didn't look like temporal epilepsy perhaps this structure deep in the brain in the temporal lobes had an effect at least encouraging in fostering epileptic seizures. so he proposed this and he carried out this operation bilaterally on hm. after that it was immediately evident that he had the same inability to remember. he was in the hospital. he could not learn the way to the bathroom though he preserved all the means of ward life, that's to quote dr. scofield, he remained the plight, gentle calm pleasant young than that he was. and he knew dr. scofield because he had known dr. scofield for many years but he did not remember the residents or the people who had been with him just around the time. >> how long did you work with him, brenda. >> i met him in 1955, which was a year and-a-half after the

surgery. i used to go down to hartford and test him. we had him in montreal for a week. >> did he remember you at any time. >> oh, no, he never. even when i would go down to hartford and typically would spend three days. and during those three days, i could spend a session with him that we're talking across this table, i was talking and working with him and i would go back and it would be after lunch i would meet him and he would just look plankly. i want to exercise he was an extremely plight person. >> how did you discover there was any memory capability. >> well the challenge for me was whether he could learn something, you know. this was obviously a challenge. you can't just say, you can't learn until you've tried. so i would go to the, over to the psychology department at mcgill. i was in montreal and pick up three tests i would choose two or three tests, take the night train to hartford, spend three

days working with hm and i would be putting his papers, going through all sorts of tests. various learning tests. >> what did you find. >> among those tests, i chose a motor learning task, amongst them. and also something that always intrigued me about them. somebody practicing or having lessons in tennis or golf or whatever. if you say to them, well what did you learn today this week, of course they can't tell you. moreover was the attempt to tell you in terms of performance. something that's going on. there are reasons why i chose, included a motor task, you know. i didn't know what i was going the to find. here you see a young man with this task i took which was essentially you have to give a star, shape of a star, a piece of paper with a double contour and you're asked to start at the

point of the star and trace a line keeping within the narrow confines of the star and come around to the top. that sounds easy until you realize you have to do this only seeing your hand and the star as reflected in a mirror. and so we all do terribly because you get to the points of the star and you do this kind of thing. but with practice, we gradually learn. and the amazing thing was that hm learned. now we see hm's performance on the first day. what i am scoring here is the number of times he went out of the pathway and had to come back. that's an error. and you can see over those ten trials that we did on the first day, his performance is getting better. now what would i expect? i probably expect the next day he might be back with his family. look how much this has carried over and he's continuing and not knowing, you know he's done

this, but continuing. and then on day three, look at that perfect performance. it's amazing. >> he does this like charlie rose. >> the thing that really impressed me at the end was, this is one of my vivid memories, personal memories. he stood up like this and looked at what he had done and he said, he speaks rather slowly, he said well, this is a little strange, he said. i thought that that would be difficult but it seems as though i done it quite well. so this is an amazing association between, you know, his total unawareness of all the experience he lives through in three days. and the beautiful performance. and from this we speculated that maybe motor learning was mediated by some other systems in the brain. it was certainly not affected by the temporal lobe.

>> this must have inspired you, larry. >> well it was fascinating because for a long long time we thought that motor skills were special. but everything else was memory and everything else was what was attempted to do. but eventually it was discovered, there's a whole family abilities which are preserved in patients with damage in the medial temporal lobe. it's not just motor skills but also perceptual skills like learning to read up side down. patients come in to do that. the and habits, things you learn by trial and error learning to say please or thank you or learning to wash your hands before dinner, pavlovian conditions. it ended up being a major distinction to be made between what we now call declarative memory on the one happened and non-declarative memory on the other hand. declarative memory is what we mean when we use memory in every day language. that's what's prepared in hm that's what dependent's on the medial temporal lobe and that refers to our ability to

remember events in the pass. in events of that we have non-declarative memory which is a whole class of things depending on different brain systems. the nucleus, the cerebellum. >> in the case non-declarative memory and the reason it's so mysterious is as brenda said it's unconscious. it's where performance changes as a result of experience and it doesn't deserve the term memory. in the cases of non-declavive memory we don't have conscious memory content nor do we have the sense we're using memory. a nice example of this might be the development of a phobia. a person at the age of 7 gets knocked down by a large dog and then later on you could say well at least two different things have happened. on the one hand a person may remember the incident and that's declarative memory. it's a memory that can be brought to mind, it's conscious, they remember the event of the incident. but on the other hand, the person may be afraid of dogs. a lesson learned experience, a learned behavior. it's not experience of a memory it's experience as an attitude

or part of your personality. but it is a kind of memory and it depends on the aw amigula. >> it's affected by age. >> what declarative memory does weaken exoably really by aging. this is a situation where 400 different people were tested in different decades on a simple list of 15 words and asked to recognize them later. want to see a weakening across time although one has to make the point that it's not ex-- it's actually rather modest. there's a certain amount of variability in this process. we like to say as we age we become more different from each other because we age at different levels of success. and it's even true in this case that 20% of the seven year olds are performing as well as the average 30 year olds. so there is an enormous apartmenamountof difference. declarative memory is like that due to changes that takes place

in the hip campus and structural lobe. non-declarative memory tends to be more preserved, tends to be more stable. it's early, it's important, habits are important but they don't change as much across time. one thing that's important in coming to all this is importance of working with animals in order to collin ate all those sist -- deliberate eight all -- delineate all those structures for understanding his memory deficit. that couldn't addressed until weed has not animal -- we had an animal model in the primate or the monkey. >> the finding that came out of the work of these two people really indicated that memory is not a unitary function of mind. that there are different types of memories get processed in different ways and they're stored in different regions too. major major advance. >> that's the h essence of the summary we just heard. >> charlie: pick up on that

scott. >> i was trying to understand the cause of this change in medial temporal lobe function as larry has already described. as eric mentioned there are two major things one needs to consider. one is normal aging itself, just like aging affects every organ system, it also affect the brain. within the brain it's not a diffuse process, it seems to target areas of the brain. and the medial temporal lobe is one of these airs yeahs. one thing to mention is alzheimer's itself. alzheimer's disease. we know it begins in the hip campus presenting with mild forgetfulness before it sweeps in other areas of the brain, other cortical areas causing a more profound cognitive impairment something we call dimension. it' dementia. it's targeting the same general area in the brain. so an important question is can we try to disassociate those

two. one way one might imagine doing that is based on the observation that the neurons in the medial temporal lobe, the brain cells are not homogeneous, not all equivalent. you have different types of neurons organized into different parts of the medial temporal lobe. and it's because of that, because we assume that aging and alzheimer's are mechanically distant that they might target parts of the medial temporal lobe. let me illiterates descrai illu. this is an mri. the circle is the medial temporal lobe. these are zoomed in images of the medial temporal lobe. these are smri or function magnetic resonance enginething scan. they not only give you cognitive information but functional information. i color coded these engines such that color reflects less function where as warmer colors like reds reflect more function. i labelled two main areas in the

medial temporal lobe that are most relevant. we have the cortex which is the main gateway into the hipcampus and then you have the hipcampus itself. on the left you see the control subject. this is a healthy subject. on the right panel been this is a patient who has alzheimer's disease and you might pressure the 5789 of blue or dysfunction in the cortex more so than other areas of the hipcampus although over time alzheimer's does spread to include all of the hipa campus. if you look at the middle panel, that's a subject who we think have normal age memory decline. if you can appreciate the cortex is relatively preserved, the area affected by alzheimer's. instead we see the most dysfunction within the hipcampus itself. >> charlie: talk a bit more about age-related in terms of how that works and what are we learning about that. >> well i mean i think perhaps the important thing to emphasize

is that what used to be thought historically as senility is the old term used for alzheimer's dimension. it's this assumption that it happened inevitably if all of us lived long enough. there is a growing awe yearness that alzheimer's -- awe awareness that alzheimer's is a disease and it doesn't affect everyone in the population. now you have these two processes or things that seem to be targeting the hipcampus contributing to why if we just sample a group of healthy seven-year-olds many will have forgetfulness. some have the early stages of alzheimer's and some we think have normal age aing. >> an interesting point that emerges from scott's discussion is that until 50 years ago, this is a little bit of an academic issue because not that many people live to be 70 or 80. alzheimer's is now a disease we're much more aware of because many more people suffer from it because they live tush old enough to be susceptible to it. >> there's two parts.

alzheimer's is emerging as an epidemic. as larry mentioned it's relatively subtle but as more and more of us are living longer and we want to stay cognitively engaged in a rich involvement even subtle forgetfulness is a problem. and i have many patients who aren't patients at all but just people who notice subtle changes. they're not measures at all. they're healthy vibe result 80 year olds. >> charlie: changes their ability of memory. >> the important point is the limitations of studies in humans and that, if i can illustrate is one of the great utilities of turbing to an a mull models. -- turning to animal models. in the upper row is again the series of human brains we just saw. on the lower row i'm showing you the mouse hipcampus. and as larry already mentioned, there's a lot of, a remarkable amount of similarities between the structures and the

organizations of the medial temporal lobe in the mouse and in humans. i'm showing you funct shawnld mri or fmri scans of mice down below. in the lower left panel you see a controlled mowls and i'm shy lighting the cortex, the main by the way into the hipcampus. if you look now on the panel on the right, lower right, that's a mouse where we introduce a gene that causes alzheimer's, and we'll talk about this in a second. so these mice have been shown to develop alzheimer's light changes at a relatively young age and that's an advantage bought we know with certainty who has a gene and who doesn't because we introduced it and we're not confounded by age aing, confused by the age aing process because these mice are relatively young. if you look at the panel on the right i think you can appreciate the dominant side of dysfunction in these alzheimer's mouse modeled are found in the cortex very similar in patients themselves and over time it spreads to involve other areas. and now if you look at the

panel, the middle lower panel, that's the mouse who we know with certainty had normal age-related memory decline. this is a wild type mouse as we call it. we don't introduce any genes, we just follow it across the life span which is two years. we can image the hipcampus and the medial temporal lobes. again you can see in the middle lower panel it's relatively preserved and the sites that are targeted are within the hipcampus itself. we're starting to see this nice association between alzheimer's and aging and perhaps to get to your question, we can use that information to get it underlying mechanism. in other words in the mouse that has alzheimer's that is expressed in every part of the brain. if there's one part of the brain it seems to be differentially vulnerable or particularly vulnerable. why is that. what is it about the cortex that makes it vulnerable. if we can understand that question. >> which brings us to understanding genes and the impact they have on these

disorders. >> actually my story, listening to brenda, my score is you just hear exceptional patients and people who give of themselves really and their families who make this research happen. so the first for me the story started with with a family i'll show you in the first image. a woman who wrote to me about her family, she's called carl jennings, she's still a friend of mine. she wrote to me about her family and in her family was an exceptional time of alzheimer's disease. what we think of as alzheimer's disease is latent alzheimer's pea disease people in their 70's and 80's. in carol's family the age of

onset was about 55 years old. so multiple generations where the family had got alzheimer's disease in their 50's. actually i know of other families, subsequent to her family where people get sick in their mid 30's with halz hierms disease. the -- alzheimer's disease. the record is someone in their late 20's with familial alzheimer's disease. of course it's terrible to be in these families in many ways but they really offer the opportunity to try and understand what causes the disease in those families. in carol's family, what we can see is the three generations affected by disease. we see that her great grandfather had the disease and her grandfather and great uncle both had the disease. >> the red images show the disease and the yellow ones. >> squares are men, circles are

women and for obvious reason sort of thing. red is affected, yellow is unaffected. and what you can see here is three generations. carol is one generation below these three generations. so you see the great grandfather had the disease. the great grandmother was fine. they had two sons both of whom had alzheimer's disease like i said in the 50's. and then in the main branch of the family, you can see five out of ten children had alzheimer's disease all at the same time. so all of the five siblings had the disease at the same time. and in the small branch of the family, the cousins, one cousin was sick out of three. so we had six affected individuals and seven unaffected individuals in that generation. what we did was actually conceptually very simple experiment. all we did was we looked at the

inheritance of the genome in those individuals and asked the question what part of the genome was inherited by all of the affected family members which their unaffected brothers and sisters. it's incredibly simple. it's not rocket science, it's really very straightforward. what we were able to see is that the smallest chromosome, chromosome 21 which you can dive down to the bottom, you can see that the five affected individuals and the affected cousin share a whole section of that chromosome. but you can also see that two of the unaffected individuals, the woman, the ninth woman on the left hand branch of the family and the middle man on the right hand branch of the family have little parts of the chromosome. but they're not safe. so that tells us the disease gene is not in the bit that

those affected cousins and siblings have. it must be between those two battle. when we looked carefully we saw the amyloid gene was in that bit, the bit inherited by the affected individuals. now in fact the amyloid gene have been identified about four years before and it had been identified because the people interested in the pathology of the disease have been keen to find out what goes wrong in the brain of people with alzheimer's disease, what proteins are deposited and they had shown the amyloid protein was deposited in the plaques. those horrible brown lumps there, they're about a tenth of a millimeter across and they are full of this amyloid peptide. so what our finding really showed was that in that family, in carol's family, the disease started with that amyloid peptide. we found a mutation in the am

employed peptide -- amyloid peptide gene which caused that protein to be deposited. so it was a very simple observation. it just tells us the disease starts with that peptide. >> fantastic observation. the first gene identified that dramatically revealed memory loss the first gene identified in alzheimer's disease opened up the whole study of the disease. >> so we and others have found lots of other mutations. but so that was certainly a start. there was some great work for peter, his group in toronto. he found the families that we had not sorted out with amyloid mutations in fact had mutations in a different gene called the presenilian gene. we know now the role of the presaw nillian gene is to amyloid the protein gene. it just fitted together so beautifully and showed that all

of these rare families have mutations in the same process. and this progressio process wass which led that peptide, that protein to be deposited in the brain. so it was a great thing. i captured from brenda too the excitement you get. we all share this. the excitement you get from knowing that something for the first time. >> what's so interesting about this also is that the hip campus temporal lobe memory that's loss. memory storage for the longest time is in tack. you can get people like a great artist with halz hierms disease could -- allege hierm alzheimere could paint that because it becomes an automatic task like tennis is to you. tell me about alzheimer's disease. >> lots of difficult. as you know, that's a difficult --

>> that's why i asked you. >> that's difficult. we've been trying to work out what are the risk factors. those are some great work from do yoduke in the 90's but founde first risk factor for alzheimer's disease. typical latent disease with a gene called -- this is a great work, great break through. this is a gene involved in cholesterol metabolism. it was entirely unexpected. that was great work. we don't really understand the connection between cholesterol metabolism and alzheimer's disease but that gene i believe points to that connection. then we've had ten years of not really making much progress but just this last two years i'm proud to say back in england in particular, there's been break throughs using the new genetic technologies to try and find other genes. what we're finding in these other genes is other genes involving cholesterol metabolism actually. >> also i think it fits in to

the general pattern, one of the predictors for good memory function is good health. physical fitness and good health, levels of cholesterol and things like that. do you want to discuss this? there are number of genes that are risk factor genes and when we think about ways of modifying the risk, obviously currently we can't affect, we can't modify our genes. >> so the question is, are there other things that occur as we age perhaps that we can modify. and that perhaps goes to your question. and one, there have been a lot of interesting research into this area. but one story that's really emerging as quite elegant has to do with the way our body handles tbloo coasglucose as we age so s the main sugar, main energy source as we eat a large meal. the way the body handles glucose is the way it influences glucose in the pan therese and that allows the muscles to absorb the glucose. now it turns out as we age, all of us become insulin resistent.

that's the term used meaning the muscles are less sensitive to the insulin. what that means is the pancreas tries to crank out a little bit more insulin and glucose regulation is less steabl. if that become profound enough that becomes a type two diabetes. even without that sgz diagnosis that's an age-related process. it turns out insulin and glucose are a two-pronged problem relevant to what we're talking about. studies have shown increases in insulin are risk factors for allegalzheimer's where the gluce regulation seems to target the area of hip campus related to normal aging and linked to normal cognitive aging. so glucose part of the metabolic pathway seems to be players here and perhaps the most important thing to emphasize is there are ways in which we can modify those age-related changes.

good example is physical exercise, aerobic exercise. >> what about social engagement, what about cognitive training. >> equally important, it's extremely important to be intellectually active. and continue your career as long as you can possibly carry it on and do other things that give you intellectual pleasure. linda freed who is the dean of the school of public health at columbia is interested in cognitive function aging and she found that if you take people in their 70's and put them into elementary schools as assistance, volunteer core, their intellectual function tends to persist on a fairly high level compared to controls that don't do this. so cognitive involvement particularly in social situations is very very helpful. and certainly social involvement is extremely important. >> charlie: tell me how explain your remarkable -- >> yes, brenda. >> i have to put genes first. >> charlie: all right, genes

first. >> because, you know, my mother, had a harder life than i d lived to be 95. she worked, she was in different career altogether and she worked in teaching. she lived at the age of 88 and she had to stop because she was getting deaf which i have escaped so far. >> charlie: so genes are first. >> yes, genes are first. [laughter] >> charlie: thank you. >> well, i think engagement, i believe engagement in cognitive activities but not sultry ones for me. it's very important for me to be engaged with young people. as i say, when i was young, i liked to engage with older people across the spectrum of ages. and on some problem that -- i think my real secret is the time

so curious, i'm extremely nosey about everything. >> charlie: that's the best news i've had all day. [laughter] >> charlie: that's my profile right there. >> although i don't take formal exercise oexaminer or anything,- exercises or anything, i walk, i don't drive a car. i live near where i work. so i walk up the hill to work and i walk back and i walk all over that city. and i think i do that because i enjoy walking. >> charlie: what are you, 91? >> yes, 91. >> charlie: where is the good news in all this in terms of memory? >> there are two parts to the good news perhaps. one is that not everything worsens as we age as you mentioned. >> charlie: exactly. we haven't really explored that. there's something important happens that matches some of loss of memory which is a certain advantage. >> with some perspective,

matures, anxiety level tends to decrease. so many aspects of cognitive function that don't require memory actually mature quite well. >> memory is built so that we, even as a young person the way our memory sist term work is we're -- system work is we're going for the gist. i don't care much for the details. that makes it possible for us actually to get the gist. the older people then that's something they can do. >> in terms of the good news, right because there is some board of director news. let's be honest. >> yes, of course. >> particularly if you live with alzheimer's. so the first thing is that the earliest stages of alzheimer's is not, does not immediately cause cell death and rampant cell loss. it's really characterized by loss of synapses and i think in this program you discussed different, the differences between -- right. and i think that's a very important point because as eric and others have shown, there is

plasticity. in other words, you can regrow synapses but you can't regrow neurnses. i -- nurses.. it's obvious to say it's easier to cure or to fix a sick cell than a dead cell. so there's some good news in that. >> charlie: for a long time the motion was, i'm allowed to be the layman here. for a long time the notion was never cells die and now we're looking at it and saying synapses between neurons is where the issue is. >> that's correct. >> ultimately there is that but that's where the imaging and various techniques to try to capture the deas early as possible. that's going to be the window that's most therapeutically efficacious. >> it's not hidden away in the closet anymore. it's not hidden away in the closet. there's openness about it and that in itself was brought. it's much better to be an alzheimer's patient today than it was 25 years ago. when i used to go around and see

alzheimer's measures 25 years ago -- patients 25 years ago, they were hidden away in the back rooms of long-stay institutions. there certainly has been enormous progress. >> major major. >> charlie: real contribution. >> much better. >> charlie: and ronald reagan deserves credit for that too in terms of announcing it. >> absolutely. >> we have to remind ourselves we learned so much with subbiology and molecular biology of the ba pathways. every detail that's added gives us a potential target, gives us another way of intervention. >> many people don't pressure appreciate -- appreciate how difficult it is to get a good drug for any disease even if it's identified. huntington's is disease, we've known it for a long time. it's an essential beginning but it doesn't guarantee immediate

therapeutic efficacy. it takes a long time to develop a really useful drug. >> charlie: this man has made contributions. he's too modest to talk about it in this whole area of understanding. am i right, scott? >> absolutely. >> charlie: what would that be. how would you define? >> well i mean if we said understanding the basic mechanism of abnormality alzheimer's you have to get to the basic cellular and molecular understanding. that's what the project really began in the late 60's or eric began. he really started dissecting out this complexity of memory down to the level of the molecules and the cells and that's really been transformative. >> charlie: so what's up next time? >> next time we're going to consider the emotional brain. emotions are the instinctive forces that drive us to seek pleasure and to avoid pain. this is such an important topic. we're going to have two consecutive programs on it. in the second program we're going to consider misery,

unhappiness, anxiety. in the coming program, the first program we're going to consider how we seek pleasure and how addictive drugs coopt the pleasure system for their own purposes. it's going to be a wonderful program. >> charlie: i look forward to it. the emotional brain. next time. join us. captioning sponsored by rose communications captioned by media access group at wgbh access.wgbh.org